Effects of Adjuvant Radiation Plus Chemotherapy on Survival Outcomes in Stage III C Endometrial Cancer According to Histology: Analysis of Data from the Surveillance, Epidemiology, and End Results Database.

Purpose: To evaluate the survival benefit of radiation plus chemotherapy in adult females with stage IIIC endometrial cancer and to investigate whether the benefit varies according to histology. Methods: Data from adult females with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC endometrial cancer, who underwent at least total hysterectomy between 2010 and 2015, were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Adjuvant treatments were categorized as chemotherapy alone, chemotherapy with external beam radiation therapy (EBRT), chemotherapy with vaginal brachytherapy (VBT), or chemotherapy with EBRT+VBT. Multivariate Cox regression models, Kaplan-Meier curves, and log-rank tests were used to assess the association between treatment modality and overall survival (OS). Results: In total, 2138 cases were identified: stage IIIC1 (n = 1299 [60.8%]) and stage IIIC2 (n = 839 [39.2%]). Median OS for all patients was 48 (interquartile range [IQR] 28-70) months. Regarding adjuvant treatment, 40.5% of patients underwent chemotherapy only, followed by chemotherapy with EBRT (35.5%). Stage IIIC patients treated with chemotherapy plus radiation exhibited a significantly reduced risk for death from endometrial cancer in both univariate and multivariate analyses (P < 0.001). However, when stratified according to histology, OS also differed according to treatment modality when analyzing each histological type; combination therapy was no longer significantly different from chemotherapy alone for any histology (clear cell and carcinosarcoma). Combination therapy was associated with improved OS in patients with IIIC1 and IIIC2 disease. Similar associations were observed in patients with high-grade stage IIIC endometrioids. However, for low-grade tumors, combination therapy was no longer associated with reduced risk for death compared with chemotherapy alone. Conclusion: For patients with stage IIIC endometrial cancer, combined treatment with radiation and chemotherapy was associated with improved OS compared with chemotherapy alone. However, no survival benefit was found, and radiotherapy may be unnecessary in patients with low-grade endometrioids.

Association between HIF-1α, BNIP3, and autophagy in the chorionic villi of missed abortion.

AIM: To investigate the expression of autophagy mediated by the hypoxia-inducible factor 1α (HIF-1α)/BNIP3 signaling pathway in villus tissues of missed abortion and HTR-8/SVneo cells and to elucidate the association of HIF-1α and BNIP3 in autophagy of missed abortion. METHODS: Villus tissues from 30 healthy women with induced abortion and 35 patients with missed abortion were collected, and HTR-8/SVneo cells were cultured under hypoxia and transfected with HIF-1α-siRNA. Real-time polymerase chain reaction was utilized to measure the mRNA levels of HIF-1α and BNIP3; Western blotting was performed to determine the protein levels of HIF-1α, BNIP3, LC3 II/I, and Beclin 1 in villus tissues and HTR-8/SVneo cells. Cellular invasion activity was detected by transwell matrigel assay. The level of autophagy was confirmed by transmission electron microscopy of autophagosome formation. RESULTS: The mRNA levels of HIF-1α and BNIP3 were significantly lower in the missed abortion villi than in the induced abortion samples. The protein levels of HIF-1α, BNIP3, Beclin 1, and LC3II/I were significantly decreased in villus tissues from missed abortion, and autophagosomes were significantly decreased in villus tissues from missed abortion. Under hypoxia, the mRNA expression of HIF-1α and BNIP3 was inhibited after silencing HIF-1α by RNAi, while the protein expression of HIF-1α, BNIP3, Beclin1, and LC3II/I was significantly downregulated. The number of invading cells was significantly decreased, and autophagosomes were significantly decreased after silencing HIF-1α by RNAi in HTR-8/SVneo cells. CONCLUSIONS: Autophagy mediated by the HIF-1α/BNIP3 signaling pathway in villous trophoblast cells may be associated with the progression and development of missed abortion.

Platycodon grandiflorus Polysaccharides Alleviate Cr(VI)-Induced Apoptosis in DF-1 Cells via ROS-Drp1 Signal Pathway.

Hexavalent chromium (Cr(VI)) is a widespread heavy metal that has been identified as a human carcinogen, and acute or chronic exposure to Cr(VI) can cause organ damage. Platycodon grandiflorus polysaccharide (PGPS) is a constituent extracted from the Chinese herb Platycodon grandiflorus, which has various pharmacological effects. Therefore, the author investigated the role of PGPSt in Cr(VI)-induced apoptosis in chicken embryo fibroblast cell lines (DF-1 cells). Firstly, this study infected DF-1 cells using Cr(VI) to set up a model for cytotoxicity and then added PGPSt. Then, the intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and apoptosis rate were evaluated. The results showed that PGPSt could inhibit Cr(VI)-induced mitochondrial damage and increase the apoptosis rate. For further exploration of the mechanism of regulation of PGPSt, the ROS-Drp1 pathway was investigated. The antioxidant N-acetyl-L-cysteine (NAC) and mitochondrial division inhibitor 1(Mdivi-1) were added, respectively. The results showed that the NAC and Mdivi-1 restored abnormal mitochondrial fission and cell apoptosis. Thus, PGPSt can alleviate Cr(VI)-induced apoptosis of DF-1 cells through the ROS-Drp1 signaling pathway, which may suggest new research ideas for developing new drugs to alleviate Cr(VI) toxicity.

Survival nomogram for endometrial cancer with lung metastasis: A SEER database analysis.

Purpose: The lung is the most common distant metastatic organ in patients with endometrial cancer (EC) but is rarely reported. This study examines the association between clinical characteristics and overall survival (OS) in EC with lung metastasis. Methods: Patients with EC who had accompanying lung metastasis were selected from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017. Univariate and multivariate Cox regression were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) and assess OS outcomes related to EC with lung metastasis. A Cox proportional hazards nomogram model for OS was constructed and validated. The calibration plot, receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate the discriminative ability and clinical benefit of the novel nomogram. Kaplan-Meier curves and scatter diagram analysis were used to investigate the risk stratifications of the nomogram. Results: Overall, 1542 EC patients with lung metastasis between 2010 and 2017 were included and randomly divided into training and validation cohorts. A nomogram model was constructed using the clinical characteristics of tumor grade, histological type, surgery, adjuvant chemotherapy, adjuvant radiation, brain metastasis and liver metastasis. The concordance indexes (C-indexes) were 0.750 (95% CI, 0.732-0.767) and 0.743 (95% CI, 0.719-0.767) for the training cohort and validation cohort, respectively. Calibration plots and DCA showed good clinical applicability of the nomogram. The areas under the curves (AUCs) were 0.803 and 0.766 for 1-year and 3-year OS, respectively, indicating that the nomogram model had a stable discriminative ability. An online calculator of our nomogram is available on the internet at https://endometrialcancer.shinyapps.io/DynNomapp/. Additionally, patients in the high-risk group had a significantly worse OS than those in the low-risk group. Conclusion: An easy-to-use, highly accurate nomogram was developed for predicting the prognosis of EC patients with lung metastasis.

Zinc enzymes in medicinal chemistry.

In humans, more than three hundred diverse enzymes that require zinc as an essential cofactor have been identified. These zinc enzymes have demonstrated different and important physiological functions and some of them have been considered as valuable therapeutic targets for drug discovery. Indeed, many drugs targeting a few zinc enzymes have been marketed to treat a variety of diseases. This review discusses drug discovery and drug development based on a dozen of zinc enzymes, including their biological functions and pathogenic roles, their best in class inhibitors (and clinical trial data when available), coordination and binding modes of representative inhibitors, and their implications for further drug design. The opportunities and challenges in developing zinc enzyme inhibitors for the treatment of human disorders are highlighted, too.